This is a proposal to define the immunoregulatory capabilities of anergic B cells. Anergy in B cells is a state of nonresponsiveness resulting from chronic stimulation through the B cell receptor (BCR), occurring in the absence of T cell help and/or innate stimulation. It is a major form of tolerance among self-reactive B cells. Anergic B cells are widely viewed as nothing more than slowly dying casualties of immunological self-tolerance, and as liabilities to the physiological immune system under circumstances where anergy might be reversed by costimulation or inflammation. To the contrary, we recently found that anergic B cells are potent regulators of immunity. Our initial observation was made upon a routine adoptive transfer involving anergic Ars/A1 B cells. Ars/A1 B cells express a dual-reactive transgenic BCR that binds the hapten p-azophenylarsonate (Ars) and single-stranded DNA, which stably maintains their anergic state upon adoptive transfer. We found that when wildtype adoptive recipients of Ars/A1 B cells were immunized with foreign proteins conjugated with Ars, not only did the Ars/A1 cells fail to mount an antibody response, they also profoundly inhibited the anti-Ars antibody response by the host immune system. This inhibition was systemic, potent (10-30 fold), antigen-specific, applied to the protein carrier, applied to the secondary immune response and required relatively few Ars/A1 B cells. On the basis of this discovery, we hypothesize that anergic B cells play a natural role in maintaining self-tolerance among CD4+ T cells. In this application, we propose to use the Ars/A1 model to define the regulatory capabilities of anergic B cells. The results of this project will almost certainly open new avenues of investigation that could lead to a paradigm shift, and to novel strategies to control autoimmunity and possibly transplant rejection.